A mild and direct oxidation of dienol thioethers into ketene dithioacetals.

‘l’e&&drcmkiters. Vol. 34.No. 24.pp.3871-38741993

RkUCdi8GnatBttI8tll

A MILD AND DIRECT OXIDATION OF DIENOL THOETHERS INTO KETENE DITHIOACETALS.

Frank Freidanck, Jacques F. Maddalund,

Odile Gaonac’h and Lucette DuhameP.

Labcmtoire de Chimie Chganiiue associt?au CNRS - FaceIt de8Scienceset Techniqaca,Univasia? & Rcum, BP 118

76134- Montst Aignancc&x @mce)

Abstract: Fnnctionolized dienol thioethers reacts with 3 eq. of thiophenol at room temperature in presence of dioqygento gin directly correspondingketenedithioacetalsin highyields.

Because of their implication in the synthesis of terpenic and related natural compounds, the chemistry of functionalixed building blocks with a 4 or 5 carbon atom backbone has been largely developed’ and remain8 an area of intensive work2. In this context, we have recently pmposed3 a method providing a versatile access to 4substituted 1-phenylthio-1,3dienes,

among which dienamines 1. These synthons may be considered as fonual

equivalents of 2-methyl-butane dial (Scheme 1) in which the two aldehydes are protected as two groups of very different chemical sensitivity, viz the enol thioether and the enamhte one. Since hoth acid and aldehyde functions are encountered in terpenic systems, searching for a route to building block8 bearing masked form8 of a carboxylic acid could turn out to be a rewatding effort Scheme

1.

3

r

Ph-S yNR2 \ \

We thought a polyfunctional

m

OH’

CHO ‘r

1

1

compound such as 2 could thus be an interesting synthon since it both

retain8 the labile enamine group and features a ketene dithioaceta14; this latter, which is a function of many synthetic possibilities as recently underlined by Kold. may preserve even in relatively harsh conditions the immanent acid moiety6. However, the simple conversion of the enol thioether function directly into the ketene dithioacetal one is unknown. and litemture does not provide, to our knowledge, a smooth method to perform such an oxidation, especially in presence of the relatively fragile enamine group7. The set of functionalixed enol 8Ptwcntadbess:LabonrroYe ~-URAl310CNRS-Faculti&Plt8nn8cie UnivaGtc de Park?v - 4, av. de ro&Jvat&‘- 7%0 ParisCMCX06 (France). 3871

3872

phenylthioethers la-c, preparedfrom haloacetals f or 3b8 has thus been treated by thiophenol in presence (or absence) of dioxygen. Depending on substrate and reaction conditions, we have found the expected double additior@ (leading to 6) to compete with the oxidation into ketene dithioaceti Results am summa&d Scheme

2. as presented on Scheme 2.

in Table 1.

2. Ph-S ToMe ‘. \

4BuLi

Ph-SmM;

5

d!!&

TM:

4

3aX=Bf 3btx=Cl

I

2%

ph_s+Wiz -

ph+NR2 Ph-S \

W+ *

ph;+cHo

\ 6

2a-c

CHO 7

6a

Table 1. Reactions of thioenol ethers at room temperature with 3 eq. of aromatic thiols in THP.

Entry

substrate

Conditions

Reaction

Pmdllct

Yield (%)B

1

lab

Ph-SH

Oxidation

2a

>!I0

2

lab

AdditiCUl

6a

>70

Oxidation

2b

SO

oxidation

2c

90

Oxidation

2a+2d+Ze+2fc

SO

air, 24h Ph-SH Ar or Nq. 24h 3

lbb

Ph-SH air, 48h

4

lcb

5

lab

Ph-SH air, 48h pMeO-C&-SH air, 24h

6

lab

o-Mew-SH air, 48h

ayieldsbasedon 94 NMRspectroscopicanalysis. cdc&mintdfromNMRandMSrmalysis.

(15:25:30:3op Oxidation

2a+2d+Ze+Zfc

SO

(15:25:30:3o)d b prepmtdas a lE,3E:lZ,3E = 50% mixtm&~. d uxrehtion behveenmticqandproduc*lti esmblii

for @d-r).

3873

Itisworthemphasixingthatalldienamine

s1wehaveamriBaedarcconvcrtcdinhighyielda,ia24hin

~ofair,intothecomspoading~~dithioscetals2.The~invdvemantofdioxygenurtheoriginal oxidizing agent indeed appears when comparing entries 1 and 2. While the oxidation is the almost single mactional pathway in pmsence of air, working under an inert atmosphere makes the double add&m the major route,lenninginthistattercaseonly~osatlaated~inabsenceafany~sdectivityonthiscompound (de. = 0%). Identity of these products has been established on the basis of 200 MHz NMR analysis and hydrolysis (1N HCl, RT) of 6s and 2a into c-g

aldehydes 7 and 8, respectively (Scheme 2). On the

other hand, simply stirring 6a for 24h in THF solution under air leads quantitatively to the same ketene dithioacetal2a. strongly suggesting that the addition reaction is reversible while the oxidation one is ineversible in these condition@. The selective hydrolysis of the enamine group in 1 illustrates the ease with which the two functions may Independently be unblocked, as requited for convenient application of this synthon. Use of other aromatic thiols has yielded results summa&d

in Scheme 3 and Table 1. A mixture of the

four possible ketene dithioacetals was obtained with p-methoxyhenrenethiol or o-thiisol,

in ratios depending

on relative pmportions ofreagents and time (entries 5 and 6). Formation of symmetrical ketene dithioacetals 2a and 2d is specially noteworthy since treatment of 28 by 3 eq. p-thioanisol leads to recovering of the starting material only, indicating

that aryl-thio exchange takes place before the oxidation

step. Bulky o,o’-

dichlorothiophenol is sluggish and leads to three oxidation products only, while 2-mercaptopyridine remains inert after 6 days. We also report the absence of reaction of la with t-butylthiol which is not only due to the large pKa difference between alkyl and aryl thiols (4.5 pK unit.@ since addition of 10% p-toluenesulfonic acid to the medium does not improve reactivity. This may be related to the easier oxidation of thiophenol when compared to t-butylthiol*. Scheme

3.

NR2

Ph-SyNR2 la

3 eq. Ar-SH

NR2

2a

2d

’ THF. Air

Ar-s NR2

+

NR2

From a stereochemical point of view, both (lE,3E) and (lZ.3E) stemoisomeric forms of dienamines 13 appear reactive and the enamine double bond C3-C4 geometry is recovued since ketene dithioacetals 2 am in each case obtained as pure E compounds, as deduced from the 13514Hx Mechanistically,

measured coupling constants11

our results am to he considered in relation to those by Oswald, Griesbaum and Hudson

concerned with radical co-oxidation of conjugated simple diolefins with thiols by dioxygen12 and to those of Yoshida et al13 dealing with the transformation of single enol thioethers.into cc-phenylthio carbunyl compounds by oxygenation in the presence of thiophenol. Likewise in our case disulfides are not the active species in this reaction since treating dienamine la with various amounts of diphenyl or di-t-butyl disulMe in absence of air and, eventually, in presence of acids or bases leads mainly to recovering of the starting material. This same result was observed using 3 eq. of sodium thioplenate in a mixture of THF and ethanol. We think the preliminary results presented here constitutes an unprecedented access to the ketene

REFERENCES AND NOTES: 1.

I&r,0. Carotenoi& Isler 0. Ed.; Birkauser Verlag Base& 1971.

2.

See inter a&x a) Kann. N.; Rein, T.; Akamark, B.; HekFdst, P. 1. Org. Chin., 1990,55,53125323.b) Duhamel. L.; Guillemont, J.; Le Gallic. Y.; PI&,G.; Pokier, J.M.; Ramondenc. Y.; Chaba&s, P. Tetrahedron Let., 1990,31,3129-3132. c) Beaudet, I; Parrain. J.L.; Quintatd, J.P. ibid, 1991,32, 6333-6336. d) Duhamel, L.; Guillemont, J.; Pohier, J.M. ibid, 1991,32,4495-4498 and4499-4500. e) Duhamel, L.; Ancel, J.E. Terrahedron, 1992,42,9237.

3.

a) Gaonac’h, 0.; Maddaluno, J.; Chauvin, J.; Duhamel. L. J. Org. C&m., 1991,56,4045-4048. b) Gaonac’h, 0.; Maddaluno, J.; Pld, G.; Duhamel, L. Tetrahedron L&r., 1992,33,2473-2476.

c)

Gaonac’h, 0. Ph.D. Thesis, Rouen University, 1992. 4.

For ketene dlthioacetals as protecting group in elecuophilic isopmne or butadiene building blocks see: a) Everhardus. R.H.; Gt%fmg, R.; Brandsma, L. Rec. Trav. Chim. Pays-Bas, 1978,97.69-72. b) Clint%, J.C.; Julia, S. 1. Chem. Res. (S), 1978,125. c) Nakai, T.; Mikami,K. Chem. ktt.,

1978,1243-

1244. 5.

Kolb M., Synthesis, 1990,171-190.

6.

a) Danishefsky, S.; Yan C.F.; MC Curry Jr, P.M. J. Org. C&m., 1977,42, 1819-1821. b) Chandrasekharan M.; A&an,

C.V.; Ila, H.; Junjappa, H. Tetrahedron L&f., 1990,31.1763-1766.

Synthetic usefulness of unsaturated ketene dithioacetal as dienes in q&addition

reactions has also been

reported: Danishefsky, S.; MC Kee, R.; Singh, R.K. J. Org. Chem., 1976,#I, 2934-2935. 7.

SeeRef. 4a for the only related example.

8.

Btomoacetal3a was prepared from senecialdehydew;

chloroacetal3b was provided by Rhi%re-Poulenc

Chimie. 9.

a) Peach, M.E. The Chemistry of theThiol Group. Vo1.2, Patai S. Ed.; John Wiley: London, 1974; p.

10.

2a may stand for instance a 24 h long 254 nm irradiation in THF at 35’Cwithout decomposition.

11.

Data for 2a: 1H NMR (2OOMHx,CDC13): &pm):

761. b) Crampton, M.R. Ibid, Vol. 1; p. 396. c) Capozxi, G.; Modena, G. Ibid, Vol. 2; p. 807. 2.33 (3H. s). 3.08 (4H, broad t, J = 5.OHz), 3.70

(4H, broad t, J = 5.OHz), 6.33 (lH, d, J = 13.9Hz). 6.56 (lH, d, J = 13.9Hz), 7.18 (lOH, m). 13C NMR (5OMHz. CDC13): &pm): 17.6, 48.2, 65.9, 100.4, 111.2, 124.9, 125.1, 126.8, 126.9, 127.1. 127.5, 128.4. 128.7, 137.0, 137.6, 144.0, 153.8. HRMS for C2lH=NOS2:

m/z 369.1221, found

369.1234. Attempt to chromatography 2a on silica gel led mainly to aldehyde 8. 12.

a) Oswald, A.A.; Grlesbaum, K.; Hudson Jr, B.E. J. Org. Chem., 1%3,28,2355-2361.

See also in

elation: Nederlof, P.J.R.; Moolenaar, M.J.; de Waard, E.R.; Huisman, H.O. Tetrahedron Z&r.,1976, 3175-317s. 13.

Yoshida, J.I.; Nakatani, S.; Isoa. S J. Chem. Sot. Chem. Commwt., 1988,1468-1470.

(Received in France 30 March 1993; accepted 21 April 1993)